A. Field of the Invention
The present invention relates to a method for treatment of pain and specifically relating to treatment of chronic pain, acute and chronic female specific pain and to methods for preventing disabilities related to such types of pain.
B. Description of Related Art
Pain is associated with a variety of different underlying illnesses or injuries. Pain may be either acute or chronic.
Chronic or intractable pain is often endured over many years or decades. Patients suffering from chronic pain often develop emotional problems which can lead to depression and in the worst case, attempted suicide. Long lasting pain often occurs particularly in joints, in muscles, connective tissue (e.g. fibromyalgia) and in the back. In the United States alone, chronic pain causes a loss of more than 250 million working days per year.
A patient is considered to have chronic pain when complaints thereof last longer than six months. In the course of time, chronic pain can come completely to the fore and form a independent clinical syndrome. Today most of the clinical phenomena of chronic pain syndrome are explained as a permanent excitation of spinal convergence neurons. This exictation can be provoked by either visceral or somatic afferent stimulation.
In general, brain pathways governing the perception of pain are still incompletely understood, although sensory afferent synaptic connections to the spinal cord, termed "nociceptive pathways" have been documented in some detail. In the first leg of such pathways, C- and A-fibers which project from peripheral sites to the spinal cord carry nociceptive signals. Polysynaptic junctions in the dorsal horn of the spinal cord are involved in the relay and modulation of sensations of pain to various regions of the brain, including the periaqueductal grey region (McGeer et al., 1987 Molecular Neurobiology of the Mammalian Brain, Plenum Press, NY). Analgesia, or the reduction of pain perception, can be effected directly by decreasing transmission along such nociceptive pathways. Analgesic opiates are thought to act by mimicking the effects of endorphin or enkephalin peptide-containing neurons, which synapse presynaptically at the C- or A-fiber terminal and which, when they fire, inhibit release of neurotransmitters, including substance P. Descending pathways from the brain are also inhibitory on C- and A-fiber firing.
Certain types of pain have complex etiologies. For example, neuropathic pain is generally a chronic condition attributable to injury or partial transection of a peripheral nerve. This type of pain is characterized by hyperesthesia, or enhanced sensitivity to external noxious stimuli. The hyperesthetic component of neuropathic pain does not respond to the same pharmaceutical interventions as does more generalized and acute forms of pain.
Opioid compounds (opiates) such as morphine, while effective in producing analgesia for many types of pain, are not always effective, and may induce tolerance in patients. When a subject is tolerant to opioid narcotics, increased doses are required to achieve a satisfactory analgesic effect. At high doses, these compounds produce side effects, such as respiratory depression, which can be life threatening. In addition, opioids frequently produce physical dependence in patients. Dependence appears to be related to the dose of opioid taken and the period of time over which it is taken by the subject. For this reason, alternate therapies for the management of chronic pain are widely sought after. In addition, compounds which serve as either a replacement for or as an adjunct to opioid treatment in order to decrease the dosage of analgesic compound required, have utility in the treatment of pain, particularly pain of the chronic, intractable type.
Several biochemical mechanisms may be activated by the administration of analgesic drugs to manage pain in humans, depending on the site of action of the drug. One such mechanism operates through local mediators by inhibiting pathways which generate pain-causing substances, such as prostaglandins, at the site of injury. Examples of agents that relieve pain in this way are the non-steroidal anti-inflammatory drugs (NSAIDs) which, as a class, are usually only effective against pain of low to moderate intensity. Moreover, long term use of many NSAIDs produce gastrointestinal side-effects such as ulceration and bleeding. Another mechanism to induce analgesia is through peripheral neurotransmission, such as local anesthetics, which act by blocking nerves that transmit pain signals. These drugs are delivered through injections and block other sensations in addition to pain. High doses of local anaesthetics may also have adverse effects on the heart causing arrhythmias, and in the brain producing convulsions. Pain relief may also be effected through CNS-mediated mechanisms (spinal and supra-spinal mechanisms). A number of attempts have been made to alleviate pain associated with pathological and non-pathological conditions in this way. As mentioned previously, the best known CNS-active analgesics are the narcotic opiates, such as morphine. While they are effective and potent, they often have several detrimental side effects.
Numerous studies of gender-comparative pain have been reported in the medical literature. These studies tend to establish that anatomical and physiological differences play an important role in central cholinergic activity and antinociception. Such studies are reviewed by Unruh, Pain, 65: 123-167 (1996). For example, many women experience non-pathological pain resulting from menstruation (including pre-menstrual pain), ovulation, pregnancy and childbirth. In addition, there are documented differences between the sexes in the prevalence of common recurrent pain such as headache and migraine, facial and oral pain, back pain, musculo-skeletal pain and abdominal pain. Finally, a number of pathological conditions result in greater pain experience in females than in males (Unruh, supra).
Recent reports of the involvement of central nicotinic neurotransmission in analgesia have stimulated the search for nicotinic agonists with analgesic properties. Epibatidine, a minor alkaloid from the South American poison frog Epipedobates tricolor (genus Dendrobatidae), is a potent nicotinic agonist which induces analgesia in rats and mice with a potency three orders of magnitude higher than morphine (Spande et al., J. Am. Chem. Soc., 114: 3475-3478, 1992; Bradley D., Science, 261: 1117, 1993). The analgesic effect of epidatidine appears to be mediated through agonism at CNS (spinal/supraspinal) nicotinic receptors and is independent of opioid release. Epibatidine is a potent agonist of ganglionic nicotinic receptors and elicits cardiorespiratory effects similar to those of nicotine. (Fisher et al., J. Pharmacol. Exp. Therap., 207: 702-707, 1994), severely limiting its potential as an effective drug for pain management.
Nicotinic ligands targeting relevant CNS receptors can induce analgesia by an opiate-independent mechanism with a potency much greater than that of morphine.
Metanicotine has been reported to possess high selectivity for central nicotinic receptor subtypes, as compared to peripheral ganglionic and muscular nicotinic receptors, and to elicit a dose dependent antinociceptive effect in animal studies. JPET, 279: 1422-29 (1996). See also Damaj et al. Society for Neuroscience Abstracts, Vol. 23, Pt. 1, No. 266.9 (1997).
Metanicotine has also been shown to exhibit therapeutic efficacy in the treatment of central nervous system (CNS) disorders, such as senile dementia of the Alzheimer's type and Parkinson's disease, and of inflammatory bowel disease, e.g., ulcerative colitis. See, for example, U.S. Pat. Nos. 5,212,188, 5,616,716 and 5,604,231. The entire disclosures of these three (3) patents are incorporated by reference in the present specification, as though set forth herein in full.
Insofar as is known, the use of metanicotine and structurally analogous compounds for the treatment of female-specific and/or chronic pain has not been reported previously.